Immunotherapy for Indolent (low grade) Lymphoma

An academic mentor once told me, “scientific advances are a lot like a game of baseball.”  Curious, I asked him what he meant.  He shared with me, “most advances are like getting a base hit.  Doubles happen but are not terribly common, triples are rare, home runs don’t happen all that often and genuine grand slams change the field all together.” 

As I shared with him my idea of turning off B cell receptor signaling using pills, he told me, “Jeff, it sounds like you are swinging for the fences, and for our Stanford fellows, we are happy if you just crowd the plate and get hit by a pitch…”  Oh well, I suppose everything worked out fine, and I still don't really care much for baseball.  I wanted to compile the history of home-runs in the field to highlight just where we are and point out where I think we are going.

If you look back over the last 60 years of advances cancer medicine, there are only a handful of clinical breakthroughs in low grade lymphoma (indolent) that fundamentally re-oriented our treatment strategies in the disease and upended the status quo of the time.  It hasn’t necessarily been a story of slow and steady progress.  Instead there are discrete episodes that shred through the treatment landscape and when the dust settles, the field has evolved into something new. 

Cancer is a complex beast and many discoveries have only served to show us just how little we actually know.  While the progress is now exponential, so too is the amount we realize we don’t know.  Every so often something comes along that genuinely moves the needle and patients have longer and better lives.  I am very excited about an emerging story in indolent NHL and I wanted to help put in context a story that I think we are going to hear about very soon.

Here is my short list – for the interested reader, I highly recommend the book The Emperor of All Maladies.  It was written by one of my residency training classmates at MGH and has received the Pulitzer Prize.   It is a fantastic read. 

1)  Way back in the 1940's local radiation therapy was the only treatment available.  This really didn't work well in a disease that is typically "systemic."  Since we didn't know much about radiation dosing, patients were burned and burned again until their disease became "radiation resistant" and they died of massive lymph node enlargement or complications from radiation.

 2)  In 1946 we had the introduction of "chemotherapy" which actually spun out of chemical warfare research during WWII.  (The remarkable story of America’s “Second Pearl Harbor” and the birth of chemotherapy is one of the most amazing little known stories in medicine). Patients with lymphoma were the very first to be treated with modified versions of mustard gas.  Responses were short-lived but merely 15 years after the introduction of penicillin the idea that “medicine” could treat cancer was born.

3)  In the 1950's the drug Adriamycin was isolated from a soil sample of a 13th century Italian Castle and subsequently was shown to be effective in lymphoma.  This drug became a "backbone" of many treatment strategies in lymphoma and is still commonly used today.  It is the “big red” drug that makes many lymphoma patients lose their hair but is also commonly used in breast cancer, gastric cancer, sarcoma’s and other diseases.

4)  For the next several decades, progress was built in many small steps.  New drugs were found, developed, and tested one at a time. Vincristine was isolated from the Madagascar Periwinkle, Etoposide was isolated from the “mayapple” and so forth.  Multiagent drug cocktails were assembled and tested.  When you put as many drugs together as you possibly could, you got crazy names such as M-Bacod (6 drugs), Pro-Mace-Cytabomb (8 drugs), and CODOX-M-IVAC (7 drugs).  While some of these were for more aggressive lymphomas, each had their loyal adherents and debates raged without much comparative data. That all ended however in 1993 CHOP (4 drugs) was declared the winner over several more "intensive" regimens.

5)  In 1997 we saw the introduction of rituximab in lymphoma.  This was the first time we used a therapeutic antibody (like the ones your body makes to fight the flu) to treat cancer.  Rituximab administered alone has impressive single agent activity and has become increasingly utilized as monotherapy.  It was also quickly added to CHOP to make the R-CHOP regimen.  This was the first "chemo-immuno-therapy" regimen and led to substantial improvements in long term outcome of patients with both low grade and DLBCL.  Until 2007, patterns of care data indicate that if you were going to get chemo for follicular lymphoma, 50% got R-CHOP, and another 25% got the same regimen without the Adriamycin which adds quite a punch in terms of side effects (R-CVP), and about 15% received rituximab alone.

6)  In 2008, there was a US based study of a drug that had been floating around East Germany during the entire cold war yet remained unknown to western cancer doctors.  This was the first that most US docs had heard of Bendamustine. The data was quite impressive for how effective the drug was compared to standard alternatives.   In 2009, the German lymphoma study group initially presented data at ASH comparing bendamustine-rituximab to R-CHOP in follicular lymphoma.  It was actually only published in Lancet last year.  This showed improved efficacy with bendamustine, and far reduced side effects which led to the sweeping changes in patterns of care.  Bendamustine with rituximab has upended practice patterns.  In the last two years, US patterns of care data reveals approximately 1/3 of previously untreated follicular lymphoma patients needing treatment receive Bendamustine-Ritxuximab, 1/3 receive rituximab alone, and only about 1/5 receive R-CHOP in front line treatment and virtually nobody receives it following relapse.  Fludarabine utilization is virtually gone (see attached slide presentation at the bottom of this post and my post on "How I treat follicular lymphoma). 

7)  As ASCO 2007, our lab at Stanford presented the first “pre-clinical” data showing that inhibition of B-Cell receptor signaling enzymes could have therapeutic effect in B cell malignancies.  This  theory was subsequently confirmed in a plenary session presention at ASH in 2008 utilizing the drug fostamatinib.  The discussant at the time felt that the data met the criteria for “game-changing” and put it on his list of NHL history makers.  While fostamatinib is no longer being actively developed, the proof of concept directly preceded / led to the exploration of ibrutinib and idelalisib in similar diseases.  In heavily pretreated patients, both of these drugs have approximately 50% overall response rate (size criteria for response determination, many more actually shrink and benefit – just not enough to be considered “partial response”) and average a year of benefit for responding patients.  Idelalisib was recently FDA approved in follicular lymphoma and we await data on ibrutinib in this population.  While the impact in follicular lymphoma remains an evolving story, the impact in chronic lymphocytic leukemia and small lymphocytic lymphoma is nothing short of transformative. 

8)  I believe story 8 in indolent lymphoma will be “immunotherapy."  Rarely a day goes by where I am not asked by a patient, “is there anything I can do to boost my immune system.”  While my answer has always been, “not really” a number of very important new therapies are showing that harnessing the power of the immune system to attack cancer can be extremely powerful.  Drugs have been either approved or are soon to be approved in melanoma, lung cancer, kidney cancer, and bladder cancer that help the immune system identify and destroy the cancer cells – without using chemotherapy.  Some of these are antibodies that interfere with the “on/off” switches of the immune system.  Others “re-program” T-cells using engineered viruses that can go absolutely crazy on B cells (see amazing video here).  The most accessible and perhaps most exciting of these for patients with indolent lymphoma may very well be the combination of revlimid with rituximab.  There are several very important studies that are poised to position this combination at the center of treatment pathways for patients with follicular lymphoma.

Nathan Fowler’s data from MD Anderson – link here (expecting updates at publication)

Nearly completed study in frontline follicular lymphoma Rev-Rituximab vs R-Chemo – link here

Open study of Rev-Ritux in relapsed follicular lymphoma – link here

I think of the combination of revlimid-rituximab (also called R2) as a road trip with a pot of coffee and a map.  Rituximab helps orient the immune system to go after the cancerous b cells by coating the outside of them and serving as an alarm for the T cells (like a road map).  Revlimid (lenalidomide) helps overcome what has been called T-Cell “pseudo-exhaustion” and get them to reactivate (ready for the road).  B cell cancers have a remarkable ability to “put the t cells to sleep.”  Whether though secretion of hormones, or actually manipulating the on/off switches of T cells, the cancerous B cells literally put the other half of the immune system into a post thanksgiving meal food coma.  Revlimid acts like a cold splash of water to the face for the sleepy T cells.  Not bad for a drug that really isn’t chemotherapy but is considered an “imid” for – immunomodulatory drug.

The combination has been explored in CLL.  It can be so active at times that there can be problems with tumor lysis syndrome.  The combination is not approved by the FDA in this setting and should be utilized very carefully due to the associated risks.

The combination has also been explored in follicular lymphoma with some pretty spectacular results… and that will be the subject of an upcoming post!

Thanks for reading

(Patterns of care data and a nice view of the Sisters volcanic range in Oregon from Mt Bachelor Ski area)

Treatment patterns in indolent nhl from Jeff Sharman

Rituximab monotherapy in follicular lymphoma

When patients are diagnosed with follicular lymphoma, the treating doc often uses the “eye ball” test on the CT scans, blood work, and physical exam to figure out whether or not a patient has “a lot” or “a little” follicular lymphoma.

While the “eyeball test” is an approximation that requires individual physician judgment (ie. subject to considerable error), such measurements have been codified by what we call the “GELF criteria” which is a French acronym for “groupe d’Etude des lymphomes folliculaires” (ie. French study group of follicular lymphoma).

You are considered “low tumor burden” provided you lack any node > 7cm, have less than three nodes areas > 3cm each, no B symptoms (night sweats, fever, weight loss), spleen below the belly button, circulating follicular lymphoma, or bone marrow dysfunction from involvement (and a few others).

The distinction between “low tumor burden” and “high tumor burden” is relevant because clinical trials often distinguish between such patients in terms of the appropriateness of certain therapies (see: how I treat follicular lymphoma part 1 and part 2).  Patients with “low tumor burden” follicular lymphoma have been studied in studies such as “rituximab vs watch and wait” or the Resort trial (how much rituxan alone do you need), or even the SAKK study (some rituxan vs some plus more rituxan) whereas patients with high tumor burden are more likely to be studied in chemotherapy type studies such as bendamustine-rituximab vs R-CHOP type studies or perhaps other new study designs.

I wanted to focus on the “low tumor burden” population because I was preparing a talk and thought there were a number of important statistics that such patients should be aware of.  I want to simply list them here for your consideration.  They are drawn from three main studies linked here:

Rituximab vs Watch and Wait

Resort Trial (Induction and Maintenance vs Induction and Retreatment when needed)

SAKK Trial (Four doses in one month vs eight doses in nine months)

From the study of “rituximab vs watch and wait”

Approximately 20% of patients with asymptomatic advanced stage disease can be followed for over 10 years without requiring treatment

Thus far NO study has shown that starting treatment EARLIER (ie immediately at diagnosis vs when needed) improves overall survival (very few studies have ever tried to prove this point

Patients who undergo watchful waiting may experience spontaneous regression in 12% of patients by two year mark evenly split between ones that completely disappear from CT scans and ones that partially disappear (in no case do we think the body has “cured” it, we just can’t detect it on scan

40% of patients with low tumor burden follicular lymphoma on watchful waiting will have growth of their lymphoma by two year mark.

Between 80-90% of patients with low tumor burden follicular lymphoma who receive rituximab will experience a response when evaluated several months post treatment

Between 10-30% of patients suitable for watch and wait yet receive rituximab will experience progression within 24 months (partially depends on how much rituximab is given)

Despite responses seen following rituximab, after following patients on average four years after randomization there is no apparent difference in overall survival or rates of histologic transformation between patients assigned to watch and wait versus rituximab (perhaps will change when data more mature?)

The average time a between diagnosis and disease progression when following watch and wait is approximately two years.

The patients who have most emotionally stable reaction to their lymphoma are patients who start rituximab and then continue on maintenance compared to those who take four doses and stop or those on watch and wait.

From the RESORT study (Rituxan followed by rituxan maintenance versus four doses or rituxan and rituxan re-use when needed)

In the average patient with low tumor burden indolent lymphoma who starts rituximab (whether with maintenance or reuse) it will work for about four years before something new is needed.

Patients who stay on maintenance rituxan are less likely to have disease progression, but those patients who “reuse” rituxan are often able to keep the disease under control for about same amount of time and use less rituxan (about 75% less rituxan)

From the SAKK study (which compared four doses of rituximab over one month versus eight doses over nine months in both previously treated and untreated follicular lymphoma)

If you don’t respond initially to rituxan, continuing it for four more doses doesn’t help

In previously untreated follicular lymphoma patients who respond to rituxan and get total of eight doses, almost half have not experienced any progression by 8 years compared to about a quarter of patients who only get four doses

There is a trend that does not reach the level of “statistical proof” that any patient with follicular lymphoma who gets eight doses compared to four might have better overall survival.  Caution here – not clear if this is real or statistical chance just making it look better

Long story short, you can slice and dice this info to do just about anything you want it to mean.  In my own practice, I generally start with rituximab once per week for four weeks then give one dose every other month for four more doses if I am starting rituximab alone in previously untreated patients.  I would not strenuously argue with others if they did it differently.  Here are a few key slides that come from the representative papers as well as a beautiful view of Mt. Washington in the Cascades east of Eugene

Rituximab Therapy in Follicular Lymphoma from Jeff Sharman

Idelalisib (Zydelig) Update

A funny thing happened when the Europeans evaluated the same trial data that led to the approval of idelalisib in the US.  They saw things differently....

Doctors and patients alike are quite interested in knowing the "package insert" for a medication.  Essentially it contains the prescribing information on how to use the drug and for what conditions it is approved.  This is enormously important because it often determines when an insurance company will have to pay for it to be used.

The US FDA and the European Commission on Medicinal Products look at new drugs independently.  They look at all the safety of all the clinical trials and the efficacy and come to their own conclusions about when such a drug could / should be used.

The FDA took a very conservative view of the trial data and highlighted the risks and gave a fairly narrowly defined set of circumstances where the drug can be used. 

In the US - the FDA has stated that it can be used in patients with CLL:
1) in combination with rituximab in patients who are not suitable for chemotherapy on account of other medical problems.

In Europe - idelalisib has been recommended for approval:
1) in combination with rituximab in patients who have had one prior line of therapy (sounds very similar to the information for ibrutinib)
2) in front line treatment for patients with 17P deletion or TP53 mutation.
     2a)  The best way to test for TP53 mutation linked here
     2b)  See my link for the new molecular markers
     2c)  There is a clinical trial in US utilizing idela/rtx in this same population that can be accessed through our network at these locations

The labeled indications for follicular lymphoma following two prior lines of therapy is quite similar.
The other key differences were regarding the safety of the drug.  The US prescribing information highlights the risks of a variety of side effects.  Things that happened to 1-2 patients (and may have due to entirely other medications) out of the 1000 treated prior to approval were listed as "black box" warnings.  It appears that several of those will be stripped entirely from the European guidelines - will try to update link when it becomes available.

"package inserts" can be "living documents."  They get updated as new clinical trials are released.  For instance, the role for ibrutinib in patients with 17P was recently updated in the US.  I expect that the package insert for both of these agents will continue to expand over time.  I think the additional insight provided by our European colleagues shed new perspective on how and where we might think to use the drugs here in the US.

Thanks for reading.

Lymphoma and Leukemia Society

I am a huge fan of the Lymphoma and Leukemia Society. 

I personally support their mission every year, I've done triathlon's for Team In Training (one of the ways they raise funds) and when I had more time, I served on their board of directors for the Oregon chapter.  I encourage everyone who reads this blog to find some way to get involved with them.

One of my wonderful patients has found a way to support them financially by hosting an annual BBQ / silent auction / etc.  Over several years he has raised close to $100,000 on behalf of LLS.

They made a video of him and his story.  I think it is really quite good.  Even though it is a call for support, his experience gives me great hope.  I think you will enjoy watching this four minute story.

Thanks for watching.  If having difficulty loading video, watch directly on YouTube by linking here.  (Seems Internet Explorer not working well, but Firefox loads well)

Can CLL be cured?

Question for you -

What is better, 10+ years free of CLL in exchange for 6 months of chemotherapy or 10 years of a pill taken daily?  Go one step further: what if the chemo not only got rid of the disease for 10 years but actually cured some patients?

We are incredibly fortunate that there are new therapies approved by the FDA that are non-chemotherapy based - but we should be careful before abandoning something that can be extremely effective for some patients just because it is called "chemo."

Everyone desperately wants to find a cure for CLL so we need to be vigilant and avoid excessive optimism.  The idea of "curable CLL" is debatable among the researchers who study the disease.  For the purposes of this post, I need to be very clear that the difference between very long term remission and cure can become a little blurry.  At what point is a patient with no signs of leukemia considered "cured?" 

I am always careful to define "remission" when I am in the clinic.  To me, it means, "we can't see the cancer but we know that it is there."  That is very different from a cure, where one would assume it isn't.  The only thing that really distinguishes between the two is the test of time.  How much time needs to pass before you say it is no longer a remission but indeed a cure.  In CLL we have never really talked about cure before, so I guess the answer is "a long time."

When carefully identified patients are treated with FCR chemo-immunotherapy, a decent fraction of them may not have any evidence of their CLL for over a decade.  Two studies have now shown statistical outcomes to suggest that some of these patients may be cured (link here and here).  

Frequent readers of my blog likely know that I have periodically taken a skeptical view of the FCR regimen.  The multitude of new drugs such as ibrutinib and idelalisib have forced us to fundamentally re-think the best ways to treat the disease.  After the widespread introduction of bendamustine and rituximab followed by the newer agents, the enthusiasm for FCR has been steadily diminishing.  Database analysis would indicate that it is only utilized in the front line management of patients with CLL in about 20-35% of patients,

I think it is human nature to embrace things that are new and exciting - especially when that means moving away from chemotherapy.  Yet as pendulums swing away from FCR 14 years after it was initially introduced, we may be ignoring some of the most impressive arguments in favor of the regimen that are only just now becoming evident. 

The "chemoimmunotherapy regimens" such as FCR and Bendamustine-rituxan have constituted our treatment backbone for a number of years.  Please see my prior blog post about choosing between the two.  With the new non chemotherapeutic targeted drugs that are coming, there is likely to be quite a "turf war" over what regimens are right in which circumstances.  While the new drugs are primarily approved in patients with relapsed disease, there will be considerable interest in moving them to the front line setting.  Indeed, I've already had quite a few patients ask me if starting with one of the new drugs up front makes more sense than chemotherapy.  I think that in some cases the answer may be yes, in other cases no.  In many cases it is too early to tell.

So where is all this going?

CLL is biologically heterogeneous.  Two patients who look very similar can have very different outcomes with treatment.  Understanding that biologic heterogeneity is essential if you want to make the best choices on behalf of the patient.  At the extremes, I think there are some patients where we need to make every effort to give effective chemoimmunotherapy and others where starting with a targeted agent makes more sense.  Between those two extremes there is a lot of uncertainty.  Over the next several blog posts, I hope to make that spectrum clear.

Let me start by coming back to the question that I began this post with:  If you could get six months of chemotherapy and have 10 years free of disease and not require any treatment, would that be better than taking pills every day for ten years?  What if I upped the ante and asked if that same six months of therapy cured a decent proportion of molecularly defined patients?  Would chemotherapy be preferable to pills in that circumstance?   What fraction of patients would need to be cured?  Would 20% be enough?  What if it was 60%?  If 80% could be cured, would that make chemotherapy better than pills that are not thought to result in cure for anyone (yet)?

Let's start by defining "cure."

When we evaluate the performance of a new drug or a regimen, we plot the efficacy on a "Kaplan Meier" curve.  On the "Y axis (up and down)" is a variable such as overall survival, or progression free survival.  On the "x-axis (left to right)" is time.  At time point zero the curve should be at 100% but then it keeps going down every time someone has an "event" such as disease progression or death.  If a disease is really bad or a treatment really ineffective, the curve goes down very quickly toward the  x-axis.  If a disease is mild, or the treatment very effective, the curve stays very "flat" and doesn't drop from 100 much. 

People who look at Kaplan Meier curves a lot get really excited when they see a "plateau."  A plateau happens when you do some sort of treatment that is likely to cure a subset of patients.  As time goes on, all those patients who are not cured either relapse or die until you are left with those patients who no longer have the disease and the events stop happening.  When this happens, the curve may start at 100, slowly drop down to the percentage of cured patients (20%?-40%?) and then stays flat - or reaches a "plateau."  If a plateau persists with updates of the data, researchers start to ask if those patients who are no longer relapsing are cured of their disease - particularly if you test them with MRD testing and they remain negative for CLL.  Of course if you follow all patients long enough, it will always go down to zero as patients die of other causes, but few studies follow patients that long and a prolonged plateau is suggestive of something very important when considering a treatment.

At ASH 2012, the MDAnderson group put out an abstract entitled, "Is CLL still incurable?"  This provocative question was asked in response to an apparent plateau in their long term follow up of the original 300 patient sample treated with FCR.  After following their original group of patients treated back in 2000-2003 for thirteen years, a group of them still appear to have no evidence of any active CLL.  That is a very impressive result for a therapy that only lasts six months.

Many researchers however regard data from MDAnderson with a degree of skepticism.  It says a lot about a patient if they get on a plane and fly down to Houston for an opinion.  It says even more if they do that every month for six months to get treated.  Such patients necessarily have a degree of affluence, fitness, and education that makes them different from the average CLL patient.  Multiple different studies have shown that such variables strongly influence outcome.  It ends up being a biased sample set.  Indeed, the average age of patients in the study was 57 years old while the average age of a patient requiring treatment for CLL in the United States is typically 74 years.  That is a massive difference.

I have to admit, I was somewhat dismissive of the 2012 abstract on that basis - until the Germans gave an update of the CLL8 study which compared FC (fludarabine / Cytoxan without rituximab) versus FCR and evaluated outcome on the basis of molecular risk factors.  They show that after six years of average follow up, several groups of patients start to achieve a plateau.  Over the ensuing two years of follow up, if a patient has not already experienced a progression, very few such patients appear likely to do so.

Is this a cure?  It is still probably too early to tell for sure.  All Kaplan meyer curves are prone to becoming "unstable" the farther out in time that you go.  Since fewer patients of the original cohort have been followed that long, single patient changes in status can have disproportionately larger effects on the curve than happens earlier in the follow up.  Furthermore, bias influences become larger if there is a subset of patients with "better" follow up data.  I am very interested though to see if this curve remains flat with subsequent follow up.  It appears to mirror the single center MDA experience but in a multicenter population where the data is more reliable.

So who are these patients? It is interesting to know after the fact that some patients do very well, but it is far more helpful if we know before selecting a therapy if a cure is within reach.  It would likely influence how you think about treating such a patient. 

I previously wrote a post about the mutation status of the B-cell receptor, so called IgVH mutation analysis.  The new update from the German CLL8 study did an impressive job looking at the multitude of new prognostic markers in CLL.  They showed that patients with unmutated IgVH (bad), had a substantially higher rate of other negative prognostic markers (such as NOTCH, SF3B1, TP53 mutations) compared to those patients with mutated IgVH (better) to the tune of about 43% vs 24%.  We also know from recent publications that newer technologies (next generation sequencing) can find a much higher frequency of adverse markers as it is a lot more sensitive to lower levels.  These lower levels appear to be very important because they appear to confer similar overall prognosis.  I wouldn't be surprised if "next-gen" could identify an even larger split between the IgVH mutated and unmutated groups.

Turns out that those patients with the mutated IgVH did MUCH better long term than those with unmutated IgVH.  Indeed if the plateau in their data holds, it may occur in as many as 60% of patients with mutated IgVH whereas no clear plateau is seen in patients with unmutated IgVH. 

Is 60% chance of long term disease control (maybe cure) good enough to take FCR?  It is abundantly clear that not all patients are sufficiently "fit" to receive FCR and NCCN guidelines draw the line for full dose FCR at age 70.  Are there other variables that you can look at to remove "bad actors" within this subset of better risk patients?  If you focus on the "good risk" patients with IgVH mutated BCR and then exclude the patients with 17P or 11Q or bad molecular markers such as TP53, NOTCH1, SF3B1 mutations what is the long term disease control rate in that group - certainly a lot higher than 60% - probably closer to 80-90% chance of long term disease control - possible cure in this subset of patients.

These findings are very similar to those seen by the MD Anderson group.  In their study just under 40% of patients had not experienced any progression at the 10 year point. If you look at the associated table however, it was strongly skewed in favor of those patients IgVH mutated BCR 49% vs 11%.  They did not have access to FISH or molecular markers so that information is not available.  I find it compelling though that the numbers were very similar between the two studies.  It is also interesting to note that the change in the shape of the curve occurred right around the 6-7 year mark in both data sets.  This implies that if you fit this highly favorable profile and make it that far out, your chance or progression over the next few years seems very unlikely.

The point I wish to make is this.  The new drugs are very "sexy."  It is very appealing to think of  taking a non-chemo pill rather than chemotherapy, but if I am ever a patient with CLL and IgVH mutated BCR lacking 17P/11Q/TP53/NOTCH1/SF3B1 abnormality, I will absolutely take chemoimmunotherapy because there is a VERY GOOD chance I will not have to think about my CLL for many years, and based upon these two studies, I think he plateau in the survival curve is very provocative.   

This blog post was originally intended to also talk about what I would do if I had 17P deletion, IgVH unumtated BCR, or other high risk markers but the post became too long and unwieldy.  I will tackle those possibilities in upcoming posts. 

Thanks for reading.

Predicting outcome to therapy

There is an interesting article out today via pubmed that talks about the ability to predict response to chemotherapy in CLL (summary editorial here, actual article here).

As I've been talking about quite a bit, it involves knowing the detailed molecular genetics associated with an individual patient which you can now test for.

I wanted to briefly point out the difference between "prognostic" and "predictive" biomarkers.  First of all, a biomarker is any sort of test such as a blood test, type of scan, etc that correlates with a biologic behavior.  Ideally those biomarkers can help influence treatment decisions to make more personalized treatment decisions.

"Prognostic biomarkers" give a general sense of how a patient is likely going to do with their disease.  In CLL, you might look at things like ZAP-70 or CD38 to estimate how a patients disease is going to behave over time.  You might say that they are "high risk patients" or "low risk patients" for progression / survival etc. but it doesn't necessarily tell you if a specific therapy is going to be useful.

"Predictive biomarkers" on the other hand help with specific therapeutic decisions.  They can be either positive or negative predictors.  Patients with 17P deletion for instance do not experience durable benefit from FCR therapy so in essence it "predicts" an inadequate response to this treatment.  Patients with TP53 or BIRC3 mutations have similar negative outcomes therefore these are considered "negative predictive biomarkers."

On the other hand, some biomarkers may be "positive predictive biomarkers."  I am VERY interested to find out if CLL patients with NOTCH1 mutations derive unique benefit from new research medications that target that mutation specifically.  In other cancers like melanoma or lung cancer, the presence of BRAF or EGFR mutations are required before you can even use certain meds that have very high levels of activity in those specific settings but are useless or even harmful if a patient lacks the mutation.

This particular CLL paper looks at the German CLL8 study which compared FC to FCR and was the first paper to establish a survival benefit in CLL.  It offers a wealth of new insight into the newer prognostic and predictive biomarkers that have emerged in CLL.  We find out that patients with SF3B1 mutations respond well, but experience more rapid relapse.  Patients with NOTCH1 mutations don't derive benefit from the addition of rituximab to FC.  Patients with 17P deletion / TP53 mutation and IgVH unmutated CLL have shorter survival following FCR therapy compared to patients lacking these abnormalities.

Both the technical article and the associated editorial are worth the read.

Thanks